A number of methods are known for calculating protein structure and dynamics. For a review on the application of energy functions, see Pokala N and Handel T M, “Energy functions for protein design: adjustment with protein-protein complex affinities, models for the unfolded state, and negative design of solubility and specificity”, J Mol. Biol., 2005 Mar. 18, 347(1): 203-27. For a discussion of the concept of developing a library of rotamers for use in protein design, see Lovell S C, Word J M, Richardson J S and Richardson D C, “The penultimate rotamer library”, Proteins, 2000 Aug. 15, 40(3): 389-408. To appreciate the efforts made to develop shortcuts in computational requirements, namely on the topic of hot spot prediction & correlated residues, see Tuncbag N, Salman F S, Keskin O and Gursoy A, “Analysis and network representation of hotspots in protein interfaces using minimum cut trees”, Proteins, 2010 Aug. 1, 78(10): 2283-94.
Computational protein chemistry necessarily involves many routines and shortcuts to allow limited computer resources to address complex calculations. One property of proteins, known to be useful in protein design, but difficult and expensive to understand, is the coupling of structural units pertaining to proteins, such as side-chains, backbone and ligands. In particular, mutations imply a structural change at one location of the protein that through aforementioned couplings can lead to significant structural and physical changes at a site remote to the site of mutation.
The complexity of the interactions within and between proteins necessarily means that these couplings are hard to determine and approximate computational methods have been shown to be one way to effectively approach the subject. The methods described herein address these and other problems in the field.